Biomarkers and Bacterial Pneumonia Risk in Patients with Treated HIV Infection: A Case-Control Study

Abstract

BackgroundDespite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist.MethodsWe performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls.ResultsCases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm3. Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively).ConclusionsIn patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Will expanded ART use reduce the burden of HIV-associated chronic lung disease?

“…Such elevations in HIV-infected patients predict poor clinical outcomes, including bacterial pneumonia 36 and death 37 . Similar elevations have been observed in non-HIV COPD cohorts 38 and such elevations similarly predict poor non-HIV COPD outcomes such as exacerbations of disease 39 (which are often triggered by bacterial infections) and death 40 .…”

Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial

“…The primary article for the START study reported a reduced risk of bacterial infectious disorder events and incidence of tuberculosis in the immediate-initiation group. Characterisation of the effect of early ART on the incidence of bacterial infections is important because these events are common in people living with HIV 5, 6, 7, 8, 9, 10…”

HIV and aging

“…While there is now a broad consensus that immune activation and inflammation persist in the majority of HIV-infected individuals maintaining long-term ART-mediated viral suppression – even in those that restore normal CD4+ T cell counts [23–26], and that immune activation and inflammatory markers strongly predict morbidity and mortality and even frailty in this setting [27–37], the degree to which inflammation is a direct cause of morbidity and mortality in this setting remains controversial. A prominent role of the inflammatory state in explaining the excess morbidity and mortality observed in treated HIV infection is supported by several observations.…”

“…Two recent studies determined that soluble markers of innate immune activation predicted non-AIDS events and mortality during ART-mediated viral suppression much more strongly than T cell activation and senescence [64, 65]. These studies suggest that innate immune activation may be a more relevant target for interventions than T cell activation or senescence, but there remains a myriad of potential innate immunologic pathways that could be targeted [27–37]. …”